Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Glycometabolome Team, RIKEN Global Research Cluster, Saitama, Japan.
Elife. 2017 Aug 4;6:e27612. doi: 10.7554/eLife.27612.
Mutations in the human glycanase 1 () cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which and its homologs regulate embryonic development are not known. Here we show that encodes an -glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an -glycanase enzyme.
人类糖苷酶 1 () 中的突变导致一种罕见的多系统先天性疾病，伴有全面发育迟缓。然而， 和其同源物调节胚胎发育的机制尚不清楚。在这里，我们表明 编码一种 -糖苷酶，并且与人类 NGLY1 具有高度的功能保守性。 的缺失导致类似于中肠特异性 BMP 信号缺失的发育性中肠缺陷。 突变体幼虫还表现出严重的中肠清除缺陷，这不能完全用受损的 BMP 信号来解释。遗传实验表明，Pngl 在 发育过程中主要在中胚层中需要。Pngl 的缺失导致 Dpp 同源二聚体的水平严重下降，并消除了由 Dpp 和 Tkv 同源二聚体介导的内脏中胚层中 BMP 的自调节。因此，我们的研究揭示了一种由 -糖苷酶酶介导的进化上保守的信号通路的组织特异性调节的新机制。
